|Publication number||US5824653 A|
|Application number||US 08/562,932|
|Publication date||Oct 20, 1998|
|Filing date||Nov 27, 1995|
|Priority date||Nov 28, 1994|
|Also published as||DE69515617D1, DE69515617T2, EP0717993A2, EP0717993A3, EP0717993B1|
|Publication number||08562932, 562932, US 5824653 A, US 5824653A, US-A-5824653, US5824653 A, US5824653A|
|Inventors||Vincent Beuvry, Michael Forster|
|Original Assignee||Virbac S.A.|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (4), Referenced by (74), Classifications (11), Legal Events (7)|
|External Links: USPTO, USPTO Assignment, Espacenet|
The present invention relates to a composition for the control and the treatment of parasitic infestations in Equidae and, in particular, for simultaneous control and treatment of infestations by roundworms and tapeworms in such animals.
Avermectins and milbemycins are currently used in the treatment and control of roundworms and bots in horses and ponies. However, these compounds are known to be inactive against tapeworms. The widespread use of the anthelmintic ivermectin has recently been linked to a rise in the prevalence of the equine tapeworm Anoplocephala perfoliata.
Anoplocephala perfoliata is found mainly in the caecum but tends also to cluster in the ileum near the ileocecal valve where it is associated with ulceration and reactive inflammation of the ileal wall. This clustering results in ulceration of the mucous membrane and inflammation with thickening and induration of the deeper layers of the intestinal wall. These pathological changes probably account for some cases of persistent diarrhoea and may predispose to intussusception of the ileum into the caecum or rupture of the bowel wall in the vicinity of the ileocecal valve.
It is therefore highly desirable to have a composition which has activity against both cestode and nematode infestations in Equidae and more particularly in horses.
It is accordingly an object of the present invention to provide a novel veterinary composition adapted to control both cestodes and nematodes in equine animals.
According to the invention, there is provided an anthelmintic composition for oral use comprising an effective amount of praziquantel and an effective amount of at least one anthelmintic agent selected from avermectins or milbemycins or derivatives thereof.
Indeed, trials have shown that, when praziquantel is orally administered to horses in combination with an avermectin or a milbemycin or a derivative thereof, a surprising increase of the anthelmintic spectrum is obtained due to the administration in combination. Furthermore a synergistic effect is observed to the extend that when in combination with avermectins or milbemycins the required dosage rate for praziquantel in equine animals is between 0.5 and 2.0 mg per kg of animal body weight. This synergistic activity is even higher with a paste formula.
Anthelmintic formulations containing praziquantel together with another anthelmintic such as for example levamisole, albendazole, oxfendazole, moxidectin, ivermetin, have been disclosed in the British Patent Application 2 252 730 of Ancare Distributors Limited. However, the various associations disclosed in this Patent Application are not synergistic and only increase the anthelmintic spectrum in sheep. According to Ancare Distributors Limited, the recommended dose rate of praziquantel in such associations is between 2.0 and 7.5 mg per kg of animal body weight.
According to the present invention, it has been discovered that the association between praziquantel and an avermectin or a milbemycin or a derivative thereof shows a surprising synergy in the treatment of horse tapeworms. It allowed the use of praziquantel against Anoplocephala perfoliata in Equidae at a dose rate between 0.5 and 2.0 mg per kg of animal body weight. These dosages are significantly lower than in the already described formulations.
Kitano in the European Patent Application 0 059 074 discloses associations of macrolide anthelmintic agents (avermectins) and a variety of several anthelmintic agents like benzimidazole, salicylamide and isoquinoline compounds with enhanced anthelmintic activity. However, Kitano studies on cestodes did not show any evident synergy of any association on Anoplocephala perfoliata.
According to the present invention, the activity of praziquantel against Anoplocephala perfoliata is increased in association with an avermectin or a milbemycin compound or a derivative thereof.
Moreover, the association exhibits higher synergistic activity as a paste formula which allowed a better biodisponibility of praziquantel in horses.
Praziquantel (2(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino 2,1-a!isoquinolin-4-one) is a relatively insoluble material in water and consequently the applicant has devised formulations for administration of the compound subject of this invention in the form of paste, drench, tablet or pellet.
Examples of formulations in accordance with the present invention will be described hereafter without limiting the generality of the invention as above described.
The range of active percentages of a typical formula in accordance with this invention could be as indicated thereafter:
______________________________________ Praziquantel 0.1-30% w/v and Ivermectin 0.05-5% w/v or Abamectin 0.05-5% w/v or Moxidectin 0.05-5% w/v or Doramectin 0.05-5% w/v______________________________________
and one or more of the following ingredients to enhance stability and/or other characteristics of the composition: surfactants, preservatives, viscosity agents, stabilisers, flavours and colours.
Ivermectin is a semisynthetic derivative of avermectins. Ivermectin contains at least 80% of 22,23-dihydroavermectin B1a and less than 20% of 22,23-dihydroavermectin B1b. Ivermectin is disclosed in Australian Patent 519569.
Abamectin or avermectin B1 contains at least 80% of avermectin B1a and not more than 20% of avermectin B1b. Abamectin is disclosed in Australian Patent 513641.
Moxidectin spiro (11,5-methano-2Hm13G, 17H-furo(4,3,2-pg) (2,6) benzodioxacyclo octadectin-13,2'-(2H) pyran-7-one,20,20b-dihydroxy-6'(1,3-dimethyl-T-butenyl)=4'-(methoxymino)-3',4',5',6,6',7,10,11,14,15,17a,20,20a, 20b-tetradecahydro-5'6,8,19-teramethyl-(6R-(2aZ,4E,5'S*, 6R* (E),8E,11R*,13S*,15R*,17aR*,20R*,20bS*)! is a new broad spectrum endectocide.
Doramectin (25-cyclohexyl-5-O-demethyl-25-de-1(methylpropyl)avermectin A1a is an avermectin.
According to the invention, when praziquantel is orally administered in combination with an avermectin, a milbemycin or a derivative thereof, the dosage rate of praziquantel required for efficiently treating equine animals against nematodes and more particularly against Anoplocephala perfoliata is between 0.5 and 2.0 mg per kg of animal body weight. However, it has been observed that praziquantel may be administered in higher dosage rates without adverse effects and in this regard dosage rates of up to 7.5 mg per kg of body weight have been tested.
______________________________________ABAMECTIN (AVERMECTIN B1) 0,4 gPRAZIQUANTEL 50 gDIETHYLENE GLYCOL PALMITO STEARATE 80 gSODIUM METABISULFITESORBITOL SOLUTION (NON-CRYSTALLISING) 120 gGLYCEROL FORMAL 60 mlPOLYETHYLENE GLYCOL 400 60 mlMETHYL HYDROXYBENZOATE 0,5 gPROPYL HYDROXYBENZOATE 0,05 gBENZYL ALCOHOL 10 gOAT MEAL FLOUR 300 gPURIFIED WATER q.s. to 1 liter______________________________________
The manufacture of the formulations of Example 1 is in accordance with the following procedures:
1. Heat 400 ml of purified water in a separate container to 80 degrees-85 degrees Celsius.
2. While mixing, add and dissolve methyl hydroxybenzoate and propyl hydroxybenzoate. Continue mixing until all has dissolved.
3. While mixing, add Sorbitol solution. Maintain the temperature at 70 degrees Celsius.
4. In a separate container, add glycerol formal, polyethylene glycol 400, benzyl alcohol. Start mixing while warming to 35 degrees-40 degrees Celsius.
5. While mixing, add abamectin. Continue mixing until all has dissolved. Maintain temperature at 35 degrees-40 degrees Celsius.
6. In the ointment tank, add half of the Oat Flour, the praziquantel, then start mixing. Continue mixing for 5-10 minutes until a homogeneous blended powder is formed. The add the rest of the Oat Flour and continue mixing.
7. While mixing the powders, add the solution from step 5 in a thin stream. When all is added, continue mixing until an homogenous mass is formed.
8. Melt diethylene glycol palmitostearate in a separate container. While mixing the solution form step 3, add the melted wax and continue mixing to form an homogeneous emulsion. Stop heating and mix to cool to 40 degrees-45 degrees Celsius.
9. Add and dissolve sodium metabisulphite in the emulsion.
10. While mixing the mass from step 7, add gradually and in a thin stream the emulsion from step 9. The emulsion when added should be at 40 degrees-45 degrees Celsius.
11. When all is added, continue mixing for 10-15 minutes.
12. Complete the batch to volume with purified water while mixing. Continue mixing for 30 minutes. Stop when the batch temperature is not higher than 30 degrees Celsius. Check on Specific Gravity (1.05-1.09).
13. Homogenise the batch.
14. Pack in syringes.
Combinations with other avermectins or milbemycin type compounds can be formulated in a manner similar to that of Example 1.
We use the ingredients, dosages and manufacturing process for Example 1 except for abamectin which is used in an amount of 2 g instead of 0.4 g.
We use the ingredients, dosages and manufacturing process of Example 1 except for abamectin which is used in an amount of 4 g instead of 0.4 g.
We use the ingredients, dosages and manufacturing process of Example 1 except for abamectin which is used in an amount of 8 g instead of 0.4 g.
We use the ingredients, dosages and manufacturing process of Example 1 except for abamectin which is used in an amount of 20 g instead of 0.4 g.
______________________________________IVERMECTIN 2 gPRAZIQUANTEL 50 gGLYCEROL FORMAL 250 mlTWEEN 80 120 gBENZYL ALCOHOL 30 gXANTHAM GUM 1 gPURIFIED WATER q.s. to 1 liter______________________________________
Other Avermectins such as abamectin or doramectin or milbemycins such as moxidectin may be used in place of ivermectin.
We use the ingredients, dosages and manufacturing process of Example 6 except for ivermectin which is used in an amount of 4 g instead of 2 g.
We use the ingredients, dosages and manufacturing process of Example 6 except for ivermectin which is used in an amount of 8 g instead of 2 g.
1 Tablet/200 kg body weight
______________________________________ Per Tablet______________________________________ABAMECTIN 40 mgPRAZIQUANTEL 200 mgSODIUM STARCH GLYCOLLATE 12 gHYDROXY PROPYL CELLULOSE 4 mgLACTOSE 178 mgCOLLOIDAL SILICON DIOXIDE 4 mgMAGNESIUM STEARATE 2 mg______________________________________
Other avermectins or milbemycins can be used instead of abamectin.
Trials of formulations in accordance with the present invention have been conducted in Australia.
The method of evaluating the activity of the formulation was a modified critical test (Lyons et al., 1986) which involved killing the horses 24 hours after treatment.
Efficacy is the number of worms count dead and removed versus the number of worms count alive and not removed (scolex attached for Anaplocephala perfoliata).
A trial involving abamectin paste (1 ml per 20 kg of body weight equivalent to 0.2 mg of Abamectin per kg B.W.), praziquantel paste (0.1 to 5 mg of Praziquantel per kg of body weight), and formulations in accordance with examples 1,2,3,4 and 5.
Eleven groups of ten horses per group were involved in the study. Area of origin of the horses was well known for having internal parasitism problem and specifically tapeworms (Anoplocephala perfoliata) infestation.
A high level of efficacy was demonstrated by the combination formula of Examples 2, 3, 4 and 5 against roundworms, anthropod parasites and tapeworms.
Synergistic activity of praziquantel and abamectin shows 100% removal of Anoplocephala perfoliata with 0.2 mg of abamectin per kg B.W. and 1 mg of praziquantel per kg B.W.
__________________________________________________________________________ % Efficacy Dosage % Efficacy % Efficacy % Efficacy AnoplocephalaAnthelmintic mg/kg Strongylidase Gasterophilus spp. Parascaris equorum perfoliata__________________________________________________________________________Abamectin 0.2 100 100 100 0Praziquantel 0.1 0 0 0 0Praziquantel 0.5 0 0 0 27Praziquantel 1 0 0 0 51Praziquantel 2 0 0 0 71Praziquantel 5 0 0 0 33Abamectin 0.2 100 100 100Praziquantel 0.1 39Abamectin 0.2 100 100 100Praziquantel 0.5 89Abamectin 0.2 100 100 100Praziquantel 1 100Abamecitin 0.2 100 100 100Praziquantel 2 100Abamectin 0.2 100 100 100Praziquantel 5 100__________________________________________________________________________
A trial involving Ivermectin drench (1 ml per 10 kg of body weight equivalent to 0.2 mg of Ivermectin per kg B.W.), praziquantel drench (0.5 to 2 mg of praziquantel per kg of body weight), and formulations in accordance with Examples 6, 7 and 8.
Seven groups of 6 horses per group were involved in the study. Area of origin of the horses was well known for having internal parasitism problem and specifically tapeworms (Anoplocephala perfoliata) infestation.
A high level of efficacy was demonstrated by the combination formula of Examples 7 and 8 against roundworms, arthropod parasites and tapeworms.
Synergistic activity of praziquantel and ivermectin shows 100% removal of Anoplocephala perfoliata with 0.2 mg of ivermectin per kg B.W. and 2 mg of praziquantel per kg B.W.
__________________________________________________________________________ % Efficacy Dosage % Efficacy % Efficacy % Efficacy AnoplocephalaAnthelmintic mg/kg Strongylidase Gasterophilus spp. Parascaris equorum perfoliata__________________________________________________________________________Ivermectin 0.2 100 100 100 0Praziquantel 0.5 0 0 0 21Praziquantel 1 0 0 0 43Praziquantel 2 0 0 0 59Ivermectin 0.2 100 100 100Praziquintel 0.5 68Ivermectin 0.2 100 100 100Praziquantel 1 91Ivermectin 0.2 100 100 100Praziquantel 2 100__________________________________________________________________________
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|U.S. Classification||514/30, 514/450|
|International Classification||A61K31/70, A61K31/495, A61K31/7048, A01N43/90, A61K31/365, A61K, A61K31/335|
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